Spinner Camille A, Uttenweiler-Joseph Sandrine, Metais Arnaud, Stella Alexandre, Burlet-Schiltz Odile, Moog-Lutz Christel, Lamsoul Isabelle, Lutz Pierre G
CNRS; IPBS (Institut de Pharmacologie et de Biologie Structurale); 205 route de Narbonne BP 64182, F-31077 Toulouse, France.
Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France.
Sci Rep. 2015 Nov 5;5:16269. doi: 10.1038/srep16269.
Conventional dendritic cells (cDCs) comprise distinct populations with specialized immune functions that are mediators of innate and adaptive immune responses. Transcriptomic and proteomic approaches have been used so far to identify transcripts and proteins that are differentially expressed in these subsets to understand the respective functions of cDCs subsets. Here, we showed that the Cullin 5-RING E3 ubiquitin ligase (E3) ASB2α, by driving degradation of filamin A (FLNa) and filamin B (FLNb), is responsible for the difference in FLNa and FLNb abundance in the different spleen cDC subsets. Importantly, the ability of these cDC subsets to migrate correlates with the level of FLNa. Furthermore, our results strongly point to CD4 positive and double negative cDCs as distinct populations. Finally, we develop quantitative global proteomic approaches to identify ASB2α substrates in DCs using ASB2 conditional knockout mice. As component of the ubiquitin-proteasome system (UPS) are amenable to pharmacological manipulation, these approaches aimed to the identification of E3 substrates in physiological relevant settings could potentially lead to novel targets for therapeutic strategies.
传统树突状细胞（cDCs）由具有专门免疫功能的不同群体组成，这些群体是先天性和适应性免疫反应的介质。到目前为止，转录组学和蛋白质组学方法已被用于识别在这些亚群中差异表达的转录本和蛋白质，以了解cDCs亚群的各自功能。在这里，我们表明，Cullin 5-RING E3泛素连接酶（E3）ASB2α通过驱动细丝蛋白A（FLNa）和细丝蛋白B（FLNb）的降解，导致不同脾脏cDC亚群中FLNa和FLNb丰度的差异。重要的是，这些cDC亚群的迁移能力与FLNa水平相关。此外，我们的结果有力地表明CD4阳性和双阴性cDCs是不同的群体。最后，我们开发了定量全局蛋白质组学方法，以使用ASB2条件性敲除小鼠识别DCs中的ASB2α底物。由于泛素-蛋白酶体系统（UPS）的组成部分适合进行药理学操作，这些旨在在生理相关环境中识别E3底物的方法可能会为治疗策略带来新的靶点。
